Method for preparing cyclohexyl thiazolyl phenyl carbamate

Abstract

The present application relates to methods of preparing Compound A:or a pharmaceutically acceptable salt or solvate thereof.

1 . A method for preparing Compound A: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, comprising Step (a) or Step (b): 
         Step (a): reacting Compound X with Compound Y to form Compound A: 5 
       
       
         
           
           
               
               
           
         
       
       or
 Step (b): reacting Compound X at  with Compound Y at  to form Compound A: 
 
       
         
           
           
               
               
           
         
         wherein X is —Cl, —Br, or —I and Y is 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The method of  claim 1 , comprising Step (a). 
     
     
         3 . The method of  claim 1 or 2 , wherein Step (a) is Step (a1):
 Step (a1): reacting Compound X with Compound B6 to form Compound A:   
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 1 or 2 , wherein Step (a) is Step (a2):
 Step (a2): reacting Compound X with Compound B6′ to form Compound A:   
       
         
           
           
               
               
           
         
       
     
     
         5 . The method of any one of  claims 1-4 , wherein X is —Br. 
     
     
         6 . The method of any one of  claims 1-5 , further comprising Step A4:
 Step A4: cyclization of Compound A4:   
       
         
           
           
               
               
           
         
         to form Compound A5: 
       
       
         
           
           
               
               
           
         
       
     
     
         7 . The method of  claim 6 , comprising cyclization of Compound A4 in the presence of an acid or a Lewis acid selected from ZnBr 2 , Yb(OTf) 3 ·H 2 O, Y(OTf) 3 , Sc(OTf) 3 , Zn(OTf) 2 , FeCl 2 , CoCl 2 , p-toluene sulfonic acid, and camphor sulfonic acid, or a combination thereof. 
     
     
         8 . The method of  claim 6 or 7 , comprising cyclization of Compound A4 in the presence of 2-bromo-1,1-dimethoxy-ethane; 2-bromo-1,1-diethoxyethane; 2-bromoacetaldehyde; or 2-chloroacetaldehyde; or a combination thereof. 
     
     
         9 . The method of any one of  claims 6-8 , wherein Step A4 is as follows: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The method of any one of  claims 6-9 , comprising cyclization of Compound A4 in the presence of ZnBr 2 , Yb(OTf) 3 ·H 2 O, Y(OTf) 3 , or Sc(OTf) 3 , or a combination thereof. 
     
     
         11 . The method of any one of  claims 6-10 , comprising cyclization of Compound A4 in the presence of ZnBr 2 . 
     
     
         12 . The method of any one of  claims 6-11 , wherein Step A4 forms Compound A5 and Compound SP 1 : 
       
         
           
           
               
               
           
         
         wherein the wt/wt ratio in the amount between Compound A5 and Compound SP1 is at least about 50:50, at least about 55:45, at least about 60:40, at least about 65:35, at least about 70:30, at least about 75:25, at least about 80:20, at least about 85:15, at least about 90:10, at least about 92:8, or at least about 95:5. 
       
     
     
         13 . The method of any one of  claims 6-12 , wherein Step A4 forms Compound A5 and Compound SP 1 : 
       
         
           
           
               
               
           
         
         wherein the total yield of Compound A5 and Compound SP1 is at least about 40%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%. 
       
     
     
         14 . The method of any one of  claims 6-13 , further comprising one or more steps of Step A1, Step A2, and Step A3:
 Step A1: reacting Compound A1:   
       
         
           
           
               
               
           
         
         with isopropyl chloroformate to form Compound A2: 
       
       
         
           
           
               
               
           
         
         Step A2: reductive amination of Compound A2 to form Compound A3: 
       
       
         
           
           
               
               
           
         
       
       and
 Step A3: converting Compound A3 to Compound A4: 
 
       
         
           
           
               
               
           
         
       
     
     
         15 . The method of any one of  claims 1-5 , further comprising Step A4′:
 Step A4′: hydrogenation of Compound A at : 
 
       
         
           
           
               
               
           
         
         to form Compound A5: 
       
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of any one of  claims 1-15 , further comprising Step A5:
 Step A5: reacting Compound A5:   
       
         
           
           
               
               
           
         
         with a halogenating agent to form Compound X: 
       
       
         
           
           
               
               
           
         
       
     
     
         17 . The method of any one of  claims 1-5 , further comprising Step A1, Step A2, Step A3, Step A4, and Step A5:
 Step A1: reacting Compound A1:   
       
         
           
           
               
               
           
         
         with isopropyl chloroformate to form Compound A2: 
       
       
         
           
           
               
               
           
         
         Step A2: reductive amination of Compound A2 to form Compound A3: 
       
       
         
           
           
               
               
           
         
         Step A3: converting Compound A3 to Compound A4: 
       
       
         
           
           
               
               
           
         
         Step A4: cyclization of Compound A4: 
       
       
         
           
           
               
               
           
         
         to form Compound A5: 
       
       
         
           
           
               
               
           
         
       
       and
 Step A5: reacting Compound A5 with a halogenating agent to form Compound X: 
 
       
         
           
           
               
               
           
         
       
     
     
         18 . The method of  claim 16 or 17 , wherein the halogenating agent is a brominating agent. 
     
     
         19 . The method of any one of  claims 1-18 , further comprising one or more steps of Step B1, Step B2, Step B3, Step B4, and Step B5:
 Step B1: converting Compound B1 to Compound B2:   
       
         
           
           
               
               
           
         
         Step B2: converting of Compound B2 to form Compound B3: 
       
       
         
           
           
               
               
           
         
         Step B3: reducing Compound B3 to Compound B4: 
       
       
         
           
           
               
               
           
         
         Step B4: converting of Compound B4 to form Compound B5: 
       
       
         
           
           
               
               
           
         
       
       and
 Step B5: converting of Compound B5 to form Compound Y: 
 
       
         
           
           
               
               
           
         
       
     
     
         20 . The method of  claim 19 , wherein Step B5 is as follows: 
       
         
           
           
               
               
           
         
       
     
     
         21 . The method of  claim 19 , wherein Step B5 is as follows: 
       
         
           
           
               
               
           
         
       
     
     
         22 . The method of any one of  claims 1-21 , wherein Step (a) or Step (b) is carried out in the presence of a palladium catalyst. 
     
     
         23 . The method of  claim 22 , wherein the palladium catalyst is selected from: